KR970001534B1 - Sulphonylphenyl- ñô -d- thioxylosides, process for their preparation - Google Patents

Abstract

New industrial products consisting of the sulphonylphenyl- beta -D-thioxyloside compounds of formula: <IMAGE> in which:   - X denotes a sulphur atom or an oxygen atom,   - R denotes a C1-C4 alkyl group, a substituted amino group NR1R2 (where each of R1 and R2, which are identical or different, denotes a C1-C4 alkyl group, it being possible for R1 and R2 considered together to form with the nitrogen atom to which they are bonded a piperidinyl or morpholinyl group) or a phenyl group optionally substituted in the para position by a cyano group or by a halogen atom; and   - Y denotes a hydrogen atom or an aliphatic acyl group. <??>These compounds can be used in therapeutics, especially as venous antithrombotic agents.

Description

Sulfonylphenyl-β-D-thioxilloside compound and preparation method thereof

The present invention relates to a novel sulfonylphenyl-β-D-thioxilloside compound, and more particularly, to a novel sulfonylphenyl-β-D-thioxyloside compound, a preparation method thereof and antithrombosis, in particular A therapeutic use as an intravenous antithrombosis agent.

EP-B-O 051 023 describes anti-ulcer agents, platelet aggregation inhibitors and anti-thrombotic agents and benzoyl phenylosides and α-hydroxybenzyl phenyllosang derivatives as oxygen supply to the brain.

EP-A-O 133 103 also describes benzylphenylosides useful for hypocholesterolemia and hypolipidemia, some of which also have antithrombotic effects, such as the product of Example 1.

EP-A-O 290 321 describes benzoylphenylthioxylsides, α-hydroxybenzylphenylthioxyloxides and benzylphenylthioxyloside derivatives as antithrombogenic agents.

Accordingly, the present invention has found that sulfonylphenyl-β-D-thioxyloside compounds that are structurally different from the conventionally known compounds are useful for the treatment and prevention of diseases related to circulatory diseases, in particular for venous antithrombosis. Hereinafter, the present invention will be described in detail.

The present invention is selected from the group consisting of sulfonylphenyl-β-D-thioxilloside represented by the following structural formula (I).

Wherein X is a sulfur atom or an oxygen atom, R is an alkyl group having 1 to 4 carbon atoms, an substituted amino group NR ₁ R ₂ (wherein R ₁ R ₂ may be external or different, and each is an alkali having 1 to 4 carbon atoms) May be bonded to each other to form a nitrogen atom and a piperidinyl or morphonyl group) or a phenyl group which is unsubstituted or whose para position is substituted with a cyano group or a halogen atom, and Y is a hydrogen atom or an aliphatic acyl group.

Aliphatic acyl groups of 2 to 5 carbon atoms are suitable for the present invention, and are preferably CH ₃ CO groups. An alkyl group having 1 to 4 carbon atoms means a linear or branched hydrocarbon radical containing 1 to 4 carbon atoms, with a preferred alkyl group being a methyl group.

Halogen atoms are chlorine, fluorine or bromine atoms, and preferred halogen atoms are fluorine atoms. Preferred compounds of formula (I) according to the invention are those compounds wherein X is a sulfur atom.

The compound of formula (I) and its acylated compound, (i) the compound of formula (II) is obtained by acylthioxyl halide of formula (III), hyperacylated thioxylose of formula (IV), and the following formula Structural formula for one mole of the compound of formula (II) in the presence of an inactive solvent, in particular a thioxylose derivative selected from the group consisting of acylthioxyloxyl tricholoa setimidate of (V) A compound of formula (III), (IV) or (V) at a rate of about 0.6 to 1.2 moles, and (ii) if necessary, a compound of formula (I) wherein Y obtained as a result is an acyl group having from 2 to 5 carbon atoms talah to 0 ^o C and the reaction metal alcoholate at a temperature between the reflux temperature of the medium (preferably magnesium methylate or sodium methylate) carbon atoms 1 to 4 in the presence of a lower alcohol (preferably methanol) Reaction by Y is can be prepared by glycation made to obtain a compound of formula (I) H.

Wherein X and R are the same as defined above, Hal is a halogen atom such as chlorine or bromine, preferably bromine atom, Y is an acyl group, especially an aliphatic acyl group having 2 to 5 carbon atoms, preferably Is an acetyl group.

Structural formulas (III), (IV) and (V) may be in the form of α or β arrays or bimodal anomer mixtures.

The glycosylation of the compound of formula (II) is carried out with the compound of formula (III) as a starting material in the presence of a catalyst such as a salt or oxide of silver, mercury or zinc, or with a Lewis acid, in particular boron trifluoride etherate or zinc chloride. Is carried out in the presence of a compound of formula (V) as a starting material or in the presence of Lewis acid as a starting material.

The first preferred embodiment of the present invention is the presence of mercury cyanide in an inert solvent selected from polar or nonpolar solvents such as dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, benzene, toluene, xylene and mixtures thereof. And condensation of 1 mole of the compound of formula (III) with about 1.1 to 1.2 moles of acylthioxylsilyl halide of the formula (III).

Benzene / nitromethane mixture for that case, cyanide mercury of 1.1 to 1.3 between the mole exists under 0 ^o C and the reflux temperature of the reaction medium, preferably 1 to 4 hours at about 40 to 50 ^o C, preferably 2 hours (1 / It is advantageous to react 2,3,4-tri-0-acetyl-5-thio-α-D-xylopyranosylbromide in 1 / V / V).

In a second preferred embodiment of the present invention, one mole of the compound of formula (II) is converted to acylthioxyl of formula (III) in the presence of silver imidazolate and zinc chloride in an inert solvent such as methylene chloride or acetonitrile. Condensation with about 1.1 to 1.2 moles of sil halide.

At this time, silver imidazole rate of 1.5 to 1.7 mol and the reflux temperature of 0 ^o C and the reaction medium under zinc chloride 2 to the presence of 2.2 moles, preferably methylene chloride or for 24 to 48 hours at about 40 to 60 ^o C methylene chloride / It is advantageous to react 2,3,4-tri-0-acetyl-5-thio-D-xycopyyrranosilbromide in the acetonitrile mixture.

In a third preferred embodiment of the present invention, one mole of the compound of formula (II) in the presence of zinc oxide in an inert solvent such as toluene and / or acetonitrile is acylthioxyl halide of formula (II) 0.6 to Condensation with 1 mole.

In this case, 2,3,4-tri-0- in a toluene / acetonitrile mixture for 18 to 48 hours at room temperature and reflux temperature of the reaction medium, preferably about 40 to 60 ^o C in the presence of 0.5 to 1.2 moles of zinc oxide. It is advantageous to react acetyl-5-thio-D-xyloparanosylbromide.

In a fourth preferred embodiment of the present invention, 1 mole of the compound of formula (II) in the presence of boron trifluoride etherate or zinc chloride in an inert solvent such as methylene chloride or acetonitrile is acyl of the formula (V). Condensation with about 1.1 to 1.3 moles of oxilosil trichloroacetimidadate.

At this time, in the presence of 0.1 to 0.4 molar solution of borontrifluoride etherate in methylene chloride or acetonitrile or in the presence of zinc chloride, a temperature between -40 ^o C and room temperature (15 to 25 ^o C), preferably about It is advantageous to react 2,3,4-tri-0-acetyl-5-thio-α-D-cyclopyranosyltrichloroacetimidadate with methylene chloride at -20 to 0 ^o C for 1 to 5 hours. .

The product of the saccharification reaction in all of these cases is a mixture of isomers of several ratios of α and β arrays.

Separation of isomers of β-arrays is characterized by fractional crystallization or chromatography, in particular flash chromatography [WCSTILL et al., J. Org. Chem. (1978) 42) n ^o 14) 2923, chromatography on silica tubes under pressure based on the techniques described above, by means of methods known to those skilled in the art.

If necessary, the obtained derivative is subjected to deacylation reaction, in particular, deacetylation reaction, which is carried out between 0 ^° C. and the reflux temperature of the reaction medium in the lower alcohol having the corresponding alcohol metal salt and having 1 to 4 carbon atoms. Preferred lower alcohols are methanol, and the alcohol metal salt is sodium or magnesium methylate.

Preferably, the deacylation reaction can be carried out after saccharification without separating the formed acylated intermediates.

It is also possible to carry out deacylation reaction enzymatically, for example using esterases of pig liver.

To obtain an intermediate of formula (II), wherein X is S, (i) dimethylaminothiocarbamoyl chloride of formula (VI) is condensed with a compound of formula (IIa) in a strong base medium to formula (VII) After obtaining the compound of (ii) (ii) obtained by heating the compound of formula (VII) rearranged (Neumanmann rearrangement (J. Org. Chem. (1966) 31, P. 3980)) to obtain the compound of formula (VIII) (iii) the compound of formula (VIII) obtained is reacted with an alcohol metal salt, preferably sodium or magnesium methylate, in a lower alcohol having 1 to 4 carbon atoms, preferably methanol, dimethylformamide or dioxane, Obtain the compound of formula (II) which is S.

Wherein R is the same as defined in the above formula. In addition, intermediates of formula (II) wherein X is S are described in L. TESTAFERRI in Tetrahedron Letters, Vol. 21, p. The method described in 3099-3100 (1980) can also be used to obtain nucleophilic substitution of suitable halogen benzene compounds.

Some of the intermediates of formula (II) wherein X is S are novel compounds.

The compound of the following structural formula wherein R 'is a fluorine atom, bromine atom or cyano group is one of the target compounds of the present invention.

The present invention provides a therapeutic composition comprising a physiologically acceptable excipient and containing at least one compound selected from the group consisting of substances of formula (I), in which of course the therapeutically effective amount of the active ingredient It exists. Compounds of formula (I) are useful for treatment with antithrombogenic agents, especially for the prevention and treatment of venous circulatory diseases.

By using a substance belonging to the group consisting of the compound of formula (I) of the present invention, an antithrombotic agent is obtained and used to treat venous circulatory diseases. The features and advantages of the present invention will be described more clearly by the following preparation and pharmacological test results, not limited by the preparation of the present invention.

In the following preparations, when the α or β arrays were measured, they were indicated in the compound name, but they did not appear when the product was an anomer mixture of α and β arrays in an unmeasured ratio.

Preparation Example I

Ia) Preparation of 4- (phenylsulfonyl) benzenethiol

1.25 g of sodium thioethylate was added to a solution of 15 g of 1-chloro-4- (phenylsulfonyl) benzene in Preparation Solution I (0.0593 mol) in 150 ml of hexamethylphosphoramide under a nitrogen atmosphere. ^o Heated for 4 h at C then cooled and hydrolyzed in ice / water mixture. 11; ; The obtained reaction medium was extracted with ethyl acetate, and the resulting aqueous layer was poured into 4N hydrochloric acid solution at 0 ^° C. When the product formed as a precipitate, after filtration, washed with water until the pH of the wash was neutral and dried to give 13.44g (yield: 90.5%) of the target compound.

Melting Point: 117 ^o C

Ib) Preparation of 4- (phenylsulfonyl) phenyl 2,3,4-tri-0-acetyl-1,5-dithio-β-D-cyclopyranoside (Example 1)

10 g (0.0399 mol) of 1-mercapto-4- (phenylsulfonyl) benzene was added to 300 ml of a toluene / nitromethane mixture (1/1 / v / v) under nitrogen atmosphere in 10.6 g of mercury cyanide (Hg (CN) 2). After addition to the dissolved solution, the resulting mixture was stirred at 40-45 ° C. for 1 hour. If precipitation was observed, 17.7 g (0.0498 moles) of 2, 3, 4-tri-0-acetyl-1, 5-dithio-β-D-xylpyranoside were added to the mixture. After stirring at 40 to 45 ^° C. for 3.5 hours, the reaction medium became clear. The organic layer obtained was cooled at 0 ^o C with 1N hydrochloric acid solution, at 0 ^o C with a 1N sodium hydroxide solution, then washed with and saturated sodium chloride solution. The solvent was evaporated and then crystallized by adding ether to give a yellow bubble. Subsequently, 8.6 g (yield: 41%) of the title compound was obtained.

Melting Point: 159%

Α _D ²³ : 58.2 ^o (C = 0.5; CHCl 3)

Ic) Preparation of 4- (phenylsulfonyl) phenyl 1,5-dithio-β-D-xylopyranoside (Example 2)

A solution of 0.35 cm ³ of sodium methylate in methanol (3.5 mol) was added to a suspension of 6.5 g of 4- (phenylsulfonyl) phenyl 1,5-dithio-β-D-xylpyranoside in 150 ml of methanol. I was. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1.5 hours and then tetrahydrofuran 250cm ³ was added.

Amberrlite ^ⓡ IR 120 H + resin and then added to pH6 to give a clear solution. After the mixture was filtered, the solvent was evaporated off under reduced pressure. Recrystallized from methanol / water mixture (50/50 / v / v /), liquefied in ethanol / water mixture (50/50 / v / v), and lyophilized to give 3.3 g (yield: 67%) of the target compound. Got it.

Melting Point: 85 to 97 ^o C

[A] _D ²³ : 44.8 ^o (C = 0.42, Dimethyl sulfoxide)

Preparation Example II

IIa) Preparation of 1-bromo-2- (methylsulfonyl) benzene

A solution of 5 g (.0246 mol) of 1-bromo-2 (methylthio) benzene in 10 ml of methanol was cooled to 0 ^° C. under nitrogen atmosphere, and then 1.27 g of 50% 3-chloroperoxybenzoic acid (MCPBA) was added. I was. After 45 minutes of stirring at 0 ^° C., 6 g of potassium fluoride was added and then hydrolyzed for 12 hours. The obtained medium was filtered through ^Celite® , and then the solvent was evaporated, and the obtained product was purified by flash chromatography using a toluene / ethyl acetate mixture (95/5 / V / V) as an eluent. 5.63 g (yield: 97%) of the target cargo were obtained.

Melting Point: 98 ^o C

IIb) Preparation of 2- (methylsulfonyl) benzenethiol

A target compound was obtained by a method similar to Preparation Example Ia).

Melting Point: 57%

IIc) Preparation of 2- (methylsulfonyl) phenyl 2,3,4-tri-0-acetyl-1,5-dithio-β-D-cyclopyranoside (Example 3)

8.43 g (0.0251 mol) of 1-bromo-2,3,4-tri-0-acetyl-5-thio-β-D-xylpyranoside to toluene / acetonitrile (1/1 / V / V) To 90 ml was added to a mixture to which 4.3 g (0.0228 mol) of 1-mercapto-2- (methylsulfonyl) -benzene and 1.95 g of zinc oxide were added, and the resulting mixture was heated at 45 ^° C. for 2 hours. The obtained medium was filtered through ^Celite® , and then the organic layer was washed with 1N hydrochloric acid solution, 1N sodium hydroxide solution and then with water until the washing pH was neutral. After evaporation of the solvent under reduced pressure, the oil obtained was crystallized by adding ether. 5.33 g of the obtained crystal product was purified by flash chromatography using a toluene / ethyl acetate mixture (8/2 / V / V) as an eluent to obtain 4.35 g (yield: 41%) of the title compound.

Melting Point: 209 ^o C

[Α] _D ²⁰ : 38.4 ^o (C = 0.5; CHCl ₃ )

IId) Preparation of 2- (methylsulfonyl) phenyl 1,5-dithio-β-D-xylopyranoside (Example 4)

Preparation Example Ic) A target compound was obtained by a similar method.

Melting Point: 139 ^o C [α] _D ²⁰ : 38.8 ^o (C = 0.5; CH ³ OH)

Preparation Example III

IIIa) Preparation of 4- (methylsulfonyl) phenyl 2,3,4-tri-0-acetyl-1,5-dithio-β-D-cyclopyranoside (Example 5)

In a similar manner to Preparation Example IIc) a colorless oil is obtained which is crystallized with ether.

Melting Point: 105 to 100 ^o C

Α _D ²⁰ : 71 ^o (C = 0.5; CHCl ₃ )

IIb) Preparation of 4- (methylsulfonyl) phenyl 1,5-dithio-β-D-xylopyranoside (Example 6)

In a similar manner to Preparation Example Ic), the desired compound was obtained after recrystallization from a methanol / ethanol mixture.

Melting Point: 25 ^o C

Α _D ²⁰ : 19.2 ^o (C = 0.5; CH ₂ Cl ₃ / CH ₃ OH (1/1 / V / V))

Preparation Example IV

IVa) Preparation of 4- (methylsulfonyl) phenyl 2,3,4-tri-0-acetyl-5-thio-β-D-cyclopyranoside (Example 7) 1-hydroxy-4- ( Methylsulfonyl) benzene 2g (0.012 mol), zinc chloride (ZnCl2) 3.17g, 1-bromo-2,3,4-tri-0-acetyl-5-thio-β-D-xylpyranoside 4.5 A mixture of g (0.013 mol) and 3.1 g (0.0177 mol) of silver imidazolate (C ₃ H ₃ AgN ₂ ) in 70 ml of methylene chloride was heated at 50 ^° C. for 20 hours. After cooling, the reaction medium was evaporated off.

The eluate was purified by flash chromatography using a toluene / ethyl acetate mixture (3 / 1V / V), and then precipitated in ethyl ether to obtain 1.1 g (yield: 21.2%) of the title compound.

Melting Point: 168 ^o C

[Α] _D ²⁰ : -75 ^o (C = 0.6; CHCl ₃ )

IVb) Preparation of 4- (methylsulfonyl) phenyl 5-thio-β-D-xylopyranoside (Example 8)

In a similar manner to Preparation Example Ic), the target compound was obtained after freezing.

Melting Point: 180 ^o C

[Α] _D ²² : -77.2 ^o (C = 0.5; CH ₃ OH)

[Manufacture example V]

Va) Preparation of 4- (ethylsulfonyl) benzenethiol

In the same manner as in Preparation Example Ia), the target compound in the form of an oil was obtained.

[Α] _D ²⁴ : 1.5891

Vb) Preparation of 4- (methylsulfonyl) phenyl 2,3,4-tri-0-acetyl-1,5-dithio-β-D-cyclopyranoside (Example 9)

A target compound was obtained by a method similar to Preparation Example Ib).

Melting Point: 136 ^o C to 137 ^o C

[A] D23: 36.7 ^o (C = 0.45; CHCl ₃ )

Vc) Preparation of 4- (methylsulfonyl) phenyl 1,5-dithio-β-D-xylopyranoside (Example 10)

A target compound was obtained by a method similar to Preparation Example Ic).

Melting Point: 130 to 135 ^o C

[A] _D ²³ : 26.8 ° (C = 0.485; Methanol)

Preparation Example VI

VIa) Preparation of 3- (methylsulfonyl) phenyl 2,3,4-tri-0-acetyl-1,5-dithio-β-D-cyclopyranoside (Example 11)

A target compound was obtained by a method similar to Preparation Example IIc).

Melting Point: 147-150 ℃

[A] _D ²¹ : -10.5 ^o (C = 0.3; CHCl ₃ )

VIb) Preparation of 3- (methylsulfonyl) phenyl 1,5-dithio-β-D-xylopyranoside (Example 12)

A target compound was obtained by a method similar to Preparation Example Ic).

Melting Point: 169 to 172 ^o C

[A] _D ²² : -12.2 ^o (C = 0.45; Dimethyl sulfoxide)

Preparation Example VII

VIIa) Preparation of 4-[(4-fluorophenyl) sulfonyl] -benzothiol

1 g (0.00398 mol) of 4-[(4-fluorophenyl) sulfonyl] -benzeneamine in a sodium nitrile solution (302 mg in 1 ml of water) in a hydrochloric acid solution (add 1.68 ml of concentrated hydrochloric acid in 5 ml of water) at -5 ^o C. Was added to the dissolved suspension. After stirring for 5 minutes, the solution was added dropwise to a solution of 2.47 g of potassium ethylxate dissolved in 5 ml of water. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide solution and saturated hydrochloric acid solution and then dried under magnesium sulfate. After evaporation of the solvent, the residue was taken up in 15 ml of ethanol and then 1.47 g of potassium hydroxide was added and the reaction mixture was heated at 45 ^° C. for 10 minutes. This was poured into cooled water, extracted with ethyl acetate and partially purified.

The aqueous layer cooled with ice was acidified by addition of concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and then the solvent was evaporated to dryness to obtain 640 ml (yield: 60%) of the title compound.

Melting Point: 116 ^o C

VIIb) Preparation of 4-[(4-fluorophenyl) sulfonyl] -phenyl 2,3,4-tri-0-acetyl-1,5-dithio-β-D-cyclopyranoside (Example 13)

A target compound was obtained by a method similar to Preparation Example IIc).

Melting Point: 80 ^o C

[A] _D ²¹ : 48.4 ^o (C = 0.5; CHCl ₃ )

VIIc) Preparation of 4-[(4-fluorophenyl) sulfonyl] -phenyl 1,5-dithio-β-D-cyclopyranoside (Example 14)

A target compound was obtained by a method similar to Preparation Example Ic).

Melting Point: 136 to 138 ^o C

[A] _D ²¹ : 40 ^o (C = 0.5; Dimethyl sulfoxide)

Preparation Example VIII

VIIIa) Preparation of 4-[(4-methoxyphenyl) sulfonyl] -benzonitrile

6 g (0.0248 mol) of 4-[(4-methoxyphenyl) thio] -benzonitrile and 18.45 g of magnesium monoperoxyphthalate hexahydrate were added sequentially to a mixture of 120 ml of ethanol and 12 ml of water. The reaction medium was incubated at 40 ^° C. for 20 minutes, hydrolyzed in cooled water, and then the solution was filtered and the white solid was washed with water. As a result, 5.2 g (yield: 77%) of the title compound was obtained.

Melting Point: 135 ^o C

VIIIb) Preparation of 4-[(4-hydroxyphenyl) sulfonyl] -benzonitrile

A mixture of 5.12 g (0.0187 mol) of 4-[(4-methoxyphenyl) sulfonyl] benzonitrile and 21.6 g of pyridinium hydrochloride was incubated at 200 ^° C. for 2 hours. After cooling, the reaction medium was hydrolyzed in 1N hydrochloric acid solution. The precipitate formed was filtered and washed with 1N hydrochloric acid solution and washed with water until the pH was neutral. As a result, 4.5 g (yield: 99%) of the target substance was obtained in the form of a gray solid.

Melting Point: 177 ^o C

VIIIc) Preparation of 0-[(4- (4-cyanophenyl) sulfonyl) -phenyl] dimethylthiocarbamate

2.36 g (0.0097 mol) of 4-[(4-hydroxyphenyl) -sulfonyl] benzonitrile were added to a solution in which 570 mg of calcium hydroxide was dissolved in 35 ml of water. The solution was incubated at room temperature for 15 minutes, cooled to 0 ^° C., and a solution of 1.38 g of N, N-dimethylthiocarbamoyl chloride dissolved in 35 ml of acetone was added dropwise. After 4 hours, the reaction mixture was hydrolyzed in 1N hydrochloric acid, and then the solution was extracted with ethyl acetate. The organic layer was washed with water until the washing pH was medium, and then dried over magnesium sulfate and concentrated to give 3 g of the target compound (yield: 100%).

Melting Point: 158 to 167 ^o C

VIIId) Preparation of S-[(4- (4-cyanophenyl) sulfonyl) -phenyl] dimethylthiocarbamate

3 g (0.0096 mol) of d-[(4- (4-cyanophenyl) sulfonyl) -phenyl] dimethylthiocarbamate were incubated at 200 ^° C. for 30 minutes. Chromatography on silica gel using a toluene / ethyl acetate mixture (8/2 / V / V) as the eluent gave 2.29 g (yield 76%) of the title compound.

Melting Point: 140 ^o C

VIIId) Preparation of 4-[(4-mercaptophenyl) sulfonyl] benzonitrile

4.1 ml of sodium methylate (8% Na (w / v) in methanol is added to 45 ml of N, N-dimethylformamide S-[(4- (4-cyanophenyl) sulfonyl) -phenyl] dimethylthiocarba 2.25 g (0.0075 moles) of mate were added to the dissolved solution at 0 ° C. The reaction mixture was then hydrolyzed in cooled 1N hydrochloric acid solution, filtered, washed with a precipitate formed and dried, as a result, 1.54 of target compound. g (yield: 78%) was obtained.

Melting Point: 160 ^o C

VIIIf) Preparation of 4-((4-cyanophenyl) sulfonyl) -phenyl 2,3,4-tri-0-acetyl-1,5-dithio-β-D-xylpyranoside (Example 15)

A target compound was obtained by a method similar to Preparation Example Ib).

Melting Point: 194 to 195 ^o C

[Α] _D ²⁰ : 51 ^o (C = 0.5; CHCl ₃ )

VIIIg) Preparation of 4-((4-cyanophenyl) sulfonyl) -phenyl 1,5-dithio-β-D-cyclopyranoside (Example 16)

A target compound was obtained by a method similar to Preparation Example Ic).

Melting Point: 175 to 183 ^o C

[Α] _D ²⁰ : 58.6 ^o (C = 0.5; dimethyl sulfoxide)

[Manufacture example IX]

Iiia) Preparation of 4- (N, N-dimethylsulfonamidyl) phenyl 2,3,4-tri-0-acetyl-1,5-dithio-β-D-xylopyranoside (Example 17)

A target compound was obtained by a method similar to Preparation Example Ib).

Melting Point: 120 ^o C

Α _D ²⁰ : 35.4 ^o (C = 0.56; CHCl ₃ )

Ivb) Preparation of 4- (N, N-dimethylsulfonamidyl) phenyl 1,5-dithio-β-D-xylopyranoside (Example 18)

A target compound was obtained by a method similar to Preparation Example Ic).

Melting Point: 208 to 213 ^o C

[A] _D ²⁴ : 21.4 ^o (C = 0.42; Dimethyl sulfoxide)

Production Example X

VIIa) Preparation of 4- (N, N-dimethylsulfonamidyl) phenyl 2,3,4-tri-0-acetyl-5-thio-β-D-xylpyranoside (Example 19)

A target compound was obtained in a similar manner to Preparation Example IVa).

Melting point: 85 ^o C and 164 to 167 ^o C (double melting point)

[A] _D ²⁵ : -57.6 ^o (C = 0.33; CHCl ₃ )

Xb) Preparation of 4- (N, N-dimethylsulfonamidyl) phenyl 5-thio-β-D-xylopyranoside (Example 20)

A target compound was obtained by a method similar to Preparation Example Ic).

Melting Point: 205 ^o C

[A] _D ²¹ : -70.4 ^o (C = 0.27; Methanol)

Preparation Example XI

Preparation of XIa) 4-mercapto-N- (piperidin-1-yl) benzenesulfonamide

A target compound was obtained by a method similar to Preparation Example Ia).

Melting Point: 93 ^o C

XIb) Preparation of 4- (N- (piperidin-1-yl) sulfonamidyl) phenyl 2,3,4-tri-0-acetyl-1.5-dithio-β-D-xylpyranoside ( Example 21)

A target compound was obtained by a method similar to Preparation Example Ib).

Melting Point: 175 to 180 ^o C

Α _D ²² : 39.8 ^o (C = 0.425; CHCl ₃ )

XIc) Preparation of 4- (N- (piperidin-1-yl) sulfonamidyl) phenyl 1,5-dithio-β-D-cyclopyranoside (Example 22)

A target compound was obtained by a method similar to Preparation Example Ic).

Melting Point: 208 to 213 ^o C

[A] _D ²² : 23.8 ^o (C = 0.21; Methanol)

Preparation Example XII

XIIa) Preparation of 4-mercapto-N- (morpholin-1-yl) benzenesulfonamide

A target compound was obtained by a method similar to Preparation Example Ia).

Melting Point: 128 ^o C

XIIb) Preparation of 4- (N- (morpholin-1-yl) sulfonamidyl) phenyl 2,3,4-tri-0-acetyl-1.5-dithio-β-D-xylpyranoside (Example Example 23

A target compound was obtained by a method similar to Preparation Example Ib).

Melting Point: 120 to 123 ^o C

[A] _D ²² : 39 ^o (C = 0.39; CHCl ₃ )

XIIc) Preparation of 4- (N- (morpholin-1-yl) sulfonamidyl) phenyl 1,5-dithio-β-D-xylopyranoside (Example 24)

A target compound was obtained by a method similar to Preparation Example Ic).

Melting Point: 90 to 105 ^o C

[A] _D ²² : 20.4 ^o (C = 0.56; Dimethyl sulfoxide)

The compounds according to the invention are shown in Table 1 without any limitation.

The antithrombogenic activity of the product according to the present invention was shown using the test results for venous thrombosis as follows.

Hypercoagulant venous congestion was performed by the method described by WESSLER et al. (J. Applied Physiol. 1959, p. 943-946). J. HAVPMAN et al. According to the method described by Thrombosis and Haemostasis 43 (2), 1980, p, 118, the anticoagulant used a solution of active ingredient X (Xa) supplied by Flow Laboratories (71 Knat per 12.5 ml of isotonic solution).

The subjects were divided into groups of 10 rats for non-resistive male wister rats weighing 250-280 g. The test product was orally administered as a suspension in PEG 400. Thrombosis occurred 4 hours after this treatment, and the formed thrombi was removed and weighed.

The results obtained with the oral administration 3 mg / kg dose are shown in Table 1, together with the results obtained for known products of the prior art mentioned above.

Claims (5)

A sulfonylphenyl-β-D-thioxilloside compound represented by the following structural formula (I).

Wherein X is a sulfur atom or an oxygen atom, R is an alkyl group having 1 to 4 carbon atoms, a substituted amino group NR ₁ R ₂ , wherein R ₁ and R ₂ may be the same or different, each having 1 to 4 carbon atoms An alkyl group, which may be bonded to each other to form a nitrogen atom and a piperidinyl or morpholinyl group) or a phenyl group which is unsubstituted or whose para position is substituted with a cyano group or a halogen atom, and Y is a hydrogen atom or an aliphatic acyl group. The sulfonylphenyl-β-D-thioxyloside compound according to claim 1, wherein X is a sulfur atom. 3. The sulfonylphenyl-β-D-thioxilloside compound according to claim 1, wherein the aliphatic acyl group Y contains 2 to 5 carbon atoms, in particular a CH ₂ CO group. (i) a compound of the following formula (II) is converted to an acylthioxylsilyl halide of the following formula (III), an overacylated thioxylose of the following formula (IV) and an acylthioxylsilyl trichloroacet of the following formula (V) Formula (III), (IV) or (V) above for 1 mole of the compound of formula (II) in an inert solvent in the presence of a thioxylose derivative selected from the group consisting of imidate and an acid acceptor and / or Lewis acid Of a compound of formula (I) wherein Y obtained above is an aliphatic acyl group having 2 to 5 carbon atoms, if necessary, between 0 ^o C and the reflux temperature of the reaction medium. Metal alcoholate at a temperature of preferably lower alcohols having 1 to 4 carbon atoms in the presence of magnesium methylate or sodium methylate, preferably deacylated in methanol, where Y is H A method for producing a sulfonylphenyl-β-D-thioxilloside compound represented by the following structural formula (I) consisting of obtaining a compound of phosphorus structural formula (I).

Wherein X is a sulfur atom or an oxygen atom, R is an alkyl group of 1 to 4 carbon atoms, substituted amino group NR ₁ R ₂ (wherein R ₁ and R ₂ may be the same or different, each having 1 to 4 carbon atoms) An alkyl group, which may be bonded to each other to form a nitrogen atom and a piperidinyl or morpholinyl group) or a phenyl group which is unsubstituted or whose para position is substituted with a cyano group or a halogen atom, and Hal is a halogen atom such as chlorine or bromine It is preferably a bromine atom, Y is an acyl group, especially an aliphatic acyl group having 2 to 5 carbon atoms in total, and preferably an acetyl group. An intermediate compound of sulfonylphenyl-β-D-thioxyroside of formula (I), wherein X is a sulfur atom, selected from the group consisting of compounds of the formula:

In the above formula, R1 is a fluorine atom, bromine atom or cyano group.